chr14-104801414-G-A

Variant names:

• chr14-104801414-G-A
• rs1161451190
• NM_001137601.3:c.217G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001137601.3(ZBTB42):​c.217G>A​(p.Ala73Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000215 in 1,395,978 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZBTB42 NM_001137601.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.04

Genes affected

ZBTB42 (HGNC:32550): (zinc finger and BTB domain containing 42) The protein encoded by this gene is a member of the C2H2 zinc finger protein family. This protein is predicted to have a pox virus and zinc finger (POZ) domain at the N-terminus and four zinc finger domains at the C-terminus. In human and mouse, the protein localizes to the nuclei of skeletal muscle cells. Knockdown of this gene in zebrafish results in abnormal skeletal muscle development and myofibrillar disorganization. A novel homozygous variant of the human gene has been associated with lethal congenital contracture syndrome, an autosomal recessive disorder that results in muscle wasting. [provided by RefSeq, Mar 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB42	NM_001137601.3	c.217G>A	p.Ala73Thr	missense_variant	Exon 1 of 1	ENST00000342537.8	NP_001131073.1
ZBTB42	NM_001370342.1	c.217G>A	p.Ala73Thr	missense_variant	Exon 2 of 2		NP_001357271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZBTB42	ENST00000342537.8	c.217G>A	p.Ala73Thr	missense_variant	Exon 1 of 1	6	NM_001137601.3	ENSP00000409107.2
ZBTB42	ENST00000555360.1	c.217G>A	p.Ala73Thr	missense_variant	Exon 2 of 2	1		ENSP00000450673.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000693 AC: 1 AN: 144210 Hom.: 0 AF XY: 0.0000129 AC XY: 1 AN XY: 77548

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000191

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1395978 Hom.: 0 Cov.: 90 AF XY: 0.00000291 AC XY: 2 AN XY: 688152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.217G>A (p.A73T) alteration is located in exon 2 (coding exon 1) of the ZBTB42 gene. This alteration results from a G to A substitution at nucleotide position 217, causing the alanine (A) at amino acid position 73 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	0.0023	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Uncertain	-0.025	T
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.98	D;D
Vest4		0.27
MutPred		0.52		Gain of catalytic residue at A75 (P = 0.0013);Gain of catalytic residue at A75 (P = 0.0013);
MVP		0.35
ClinPred		0.95	D
GERP RS		2.9
Varity_R		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1161451190; hg19: chr14-105267751;